Gephyrin, the inhibitory synapse and pathogenic microdeletions

GABA, postsynaptic. The molecular structure of the postsynapse has long been a mystery. Why do receptors cluster at a particular site and don’t simply float around all over the plasma membrane? The identification of postsynaptic scaffolding proteins answered some of these questions. However, it also became clear that inhibitory synapses are completely different from excitatory synapses. Now, a recent paper in Human Molecular Genetics finds that exonic deletions in gephyrin, the main structural protein of the inhibitory synapse, predispose to various neurodevelopmental disorders. Continue reading

NRXN1 deletions and the double hit hypothesis of idiopathic epilepsy

Old friends. Structural genomic variants or Copy Number Variations (CNVs) play an important role in many neurodevelopmental disorders including epilepsy, autism, schizophrenia and intellectual disability. Many of the CNVs representing genetic risk factors overlap between these diseases. Now, a recent study in Epilepsia reports on the exon-disrupting deletions in NRXN1 as genetic risk factors for Idiopathic Generalised Epilepsy. NRNX1 deletions were previously reported in several other neurodevelopmental disorders. However, there is an interesting and unanticipated twist to the story. Continue reading